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Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer.


ABSTRACT: Estrogen receptor ? (ER?) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ER? is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ER?+ BCa. A phase II study suggested that bortezomib, an inhibitor blocking the activity of 20?S proteasomes, intervenes in cancer progression for anti-endocrine therapy in BCa. Here we report that proteasome-associated deubiquitinases (USP14 and UCHL5) inhibitors b-AP15 and platinum pyrithione (PtPT) induce growth inhibition in ER?+ BCa cells. Further studies show that these inhibitors induce cell cycle arrest and apoptosis associated with caspase activation, endoplasmic reticulum (ER) stress and the downregulation of ER?. Moreover, we suggest that b-AP15 and PtPT block ER? signaling via enhancing the ubiquitin-mediated degradation of ER? and inhibiting the transcription of ER?. Collectively, these findings demonstrate that proteasome-associated deubiquitinases inhibitors b-AP15 and PtPT may have the potential to treat BCa resistant to anti-hormonal therapy.

SUBMITTER: Xia X 

PROVIDER: S-EPMC6155249 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer.

Xia Xiaohong X   Liao Yuning Y   Guo Zhiqiang Z   Li Yanling Y   Jiang Lili L   Zhang Fangcheng F   Huang Chuyi C   Liu Yuan Y   Wang Xuejun X   Liu Ningning N   Liu Jinbao J   Huang Hongbiao H  

Oncogenesis 20180924 9


Estrogen receptor α (ERα) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERα is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ERα<sup>+</sup> BCa. A phase II study suggested  ...[more]

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